rs758834960

Variant names:

• chrX-41141431-A-G
• rs758834960
• NM_001039591.3:c.1161A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_001039591.3(USP9X):​c.1161A>G​(p.Ala387Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000377 in 1,060,794 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000038 (0 hom. 1 hem.)
• Consequence: USP9X NM_001039591.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.0006375
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.12
• Publications: 0 publications found

Genes affected

USP9X (HGNC:12632): (ubiquitin specific peptidase 9 X-linked) This gene is a member of the peptidase C19 family and encodes a protein that is similar to ubiquitin-specific proteases. Though this gene is located on the X chromosome, it escapes X-inactivation. Mutations in this gene have been associated with Turner syndrome. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

USP9X Gene-Disease associations (from GenCC):

• intellectual disability, X-linked 99, syndromic, female-restricted

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, X-linked 99

  Inheritance: XL Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked female restricted facial dysmorphism-short stature-choanal atresia-intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP7: Synonymous conserved (PhyloP=2.12 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039591.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP9X	NM_001039591.3	MANE Select	c.1161A>G	p.Ala387Ala	splice_region synonymous	Exon 9 of 45	NP_001034680.2
	USP9X	NM_001410748.1		c.1161A>G	p.Ala387Ala	splice_region synonymous	Exon 10 of 46	NP_001397677.1
	USP9X	NM_001039590.3		c.1161A>G	p.Ala387Ala	splice_region synonymous	Exon 9 of 45	NP_001034679.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP9X	ENST00000378308.7	TSL:5 MANE Select	c.1161A>G	p.Ala387Ala	splice_region synonymous	Exon 9 of 45	ENSP00000367558.2
	USP9X	ENST00000703987.1		c.1161A>G	p.Ala387Ala	splice_region synonymous	Exon 9 of 45	ENSP00000515604.1
	USP9X	ENST00000324545.9	TSL:5	c.1161A>G	p.Ala387Ala	splice_region synonymous	Exon 9 of 45	ENSP00000316357.6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000133 AC: 2 AN: 149959 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000988

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000377 AC: 4 AN: 1060794 Hom.: 0 Cov.: 30 AF XY: 0.00000297 AC XY: 1 AN XY: 336818

African (AFR) AF: 0.0000399 AC: 1 AN: 25051

American (AMR) AF: 0.000102 AC: 3 AN: 29305

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17861

East Asian (EAS) AF: 0.00 AC: 0 AN: 29180

South Asian (SAS) AF: 0.00 AC: 0 AN: 45415

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39093

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3922

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 826474

Other (OTH) AF: 0.00 AC: 0 AN: 44493

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	8.0
DANN	Benign	0.71
PhyloP100		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00064
dbscSNV1_RF	Benign	0.084
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs758834960; hg19: chrX-41000684;